Hepatitis C virus immune escape via exploitation of a hole in the T cell repertoire.
Hepatitis C virus (HCV) infection frequently persists despite eliciting substantial virus-specific immune responses. Thus, HCV infection provides a setting in which to investigate mechanisms of immune escape that allow for viral persistence. Viral amino acid substitutions resulting in decreased MHC binding or impaired Ag processing of T cell epitopes reduce Ag density on the cell surface, permitting evasion of T cell responses in chronic viral infection. Substitutions in viral epitopes that alter TCR contact residues frequently result in escape, but via unclear mechanisms because such substitutions do not reduce surface presentation of peptide-MHC complexes and would be expected to prime T cells with new specificities. We demonstrate that a known in vivo HCV mutation involving a TCR contact residue significantly diminishes T cell recognition and, in contrast to the original sequence, fails to effectively prime naive T cells. This mutant epitope thus escapes de novo immune recognition because there are few highly specific cognate TCR among the primary human T cell repertoire. This example is the first on viral immune escape via exploitation of a "hole" in the T cell repertoire, and may represent an important general mechanism of viral persistence.
Wölfl
Matthias
M
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Rutebemberwa
Alleluiah
A
Mosbruger
Timothy
T
Mao
Qing
Q
Li
Hong-mei
HM
Netski
Dale
D
Ray
Stuart C
SC
Pardoll
Drew
D
Sidney
John
J
Sette
Alessandro
A
Allen
Todd
T
Kuntzen
Thomas
T
Kavanagh
Daniel G
DG
Kuball
Jürgen
J
Greenberg
Philip D
PD
Cox
Andrea L
AL
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D017951:Antigen Presentation / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D006801:Humans; D009154:Mutation; D011446:Prospective Studies; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism; D017735:Virus Latency / Q000276:immunology*; D055815:Young Adult
D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins